WO2009054609A1 - Membrane de régénération osseuse et procédé de fabrication de membrane de régénération osseuse - Google Patents

Membrane de régénération osseuse et procédé de fabrication de membrane de régénération osseuse Download PDF

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Publication number
WO2009054609A1
WO2009054609A1 PCT/KR2008/004932 KR2008004932W WO2009054609A1 WO 2009054609 A1 WO2009054609 A1 WO 2009054609A1 KR 2008004932 W KR2008004932 W KR 2008004932W WO 2009054609 A1 WO2009054609 A1 WO 2009054609A1
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Prior art keywords
poly
calcium phosphate
bone regeneration
biodegradable polymer
regeneration membrane
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PCT/KR2008/004932
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English (en)
Inventor
Chang Kook You
Kwang Bum Park
Kyoung Ho Ryoo
Seok Kyu Choi
Dong Jun Yang
Hyun Wook An
Keun Oh Park
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Megagen Implant Co., Ltd.
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Publication of WO2009054609A1 publication Critical patent/WO2009054609A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
    • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
    • A61L27/48—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with macromolecular fillers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/56—Porous materials, e.g. foams or sponges
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/58—Materials at least partially resorbable by the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2430/00—Materials or treatment for tissue regeneration
    • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

  • the present invention relates to a bone regeneration membrane including: an outer layer having a porous semi-permeable structure; and an inner layer having a fiber radial mesh structure, wherein the inner layer is formed on the outer layer, and a method of manufacturing the same.
  • a bone regeneration membrane including: an outer layer having a porous semi-permeable structure; and an inner layer having a fiber radial mesh structure, wherein the inner layer is formed on the outer layer, and a method of manufacturing the same.
  • a shielding film formed of a non-biodegradable or biodegradable material is used for a derivation tissue regeneration technique or as a dressing material for skin or mucous tissue.
  • non-biodegradable material examples include expanded-polytetrafloroethylene (e-PTFE), ethyl cellulose (EC), high density polytetrafloroethylene (PTFE), freeze-dried dura mater (FDDMA), and titanium mesh.
  • e-PTFE expanded-polytetrafloroethylene
  • EC ethyl cellulose
  • PTFE high density polytetrafloroethylene
  • FDDMA freeze-dried dura mater
  • titanium mesh titanium mesh
  • biodegradable material examples include polylactic acid (PLA), collagens (collagen type I, III), polyglatin, polylactic-co-glycolic acid (PLGA), polyglycolic acid (PGA), lactide, and poly-L-lactic acid (PLLA)-polysiloxane-calcium carbonate.
  • PLA polylactic acid
  • PLGA collagens
  • PGA polyglycolic acid
  • lactide lactide
  • PLLA poly-L-lactic acid
  • these shielding films are absorbed into body and removed and thus, a second surgery is not needed.
  • these shielding films have a single layer structure and a relatively large pore size of microns. Accordingly, inflow of fibroblasts is incompletely prevented and thus, a portion of a gingiva tissue grows between filled synthesis bones.
  • the size of the fibroblast is about 5 to 15 ⁇ m- Accordingly, to completely prevent inflow of the fibroblast, the pore size should be smaller than this size range. For example, the pore size should be in nanometer levels. In addition, a pore structure that suppresses attachment of the fibroblast or amplification of a fibroblast when attached is needed. However, currently available techniques are inappropriate to realize these functions and sufficient porosity to smoothly pass blood, body fluids, and oxygen.
  • most biodegradable polymer materials have a mesh structure or a porous structure formed by tangled fibers.
  • the pore size is about 10 to 100 ⁇ m and thus, the inflow of the fibroblast cannot be prevented.
  • osteoblast since besides osteoblast, fibroblast is also easily attached, it is difficult to effectively block the gingiva tissue.
  • the present invention provides a bone regeneration membrane and a method of manufacturing the same.
  • the bone regeneration membrane prevents an inflow of a gingiva tissue or fibroblast that is an origin of the gingiva tissue so that growth of the gingiva tissue during a bone regeneration period following coverage with a synthesis bone filler is suppressed and a sufficiently stable bone regeneration obtained by growing a bio alveolar bone between filled synthesis bone powder is derived, when teeth are extracted for the purpose of implants or remedying of riodontal diseases and then an empty space is filled with a pharmaceutical synthesis bone power to regenerate bones.
  • a bone regeneration membrane according to the present invention is, unlike a conventional semi-permeable membrane having a single layer structure and a very large pore size, a semi-permeable membrane having a double-layer asymmetric structure in which outer and inner layers have different pore sizes.
  • the outer layer of the bone regeneration membrane has a dense pore structure in which fine pores are regularly arranged and thus, allows blood, body fluids, and oxygen to easily pass therethrough and effectively prevent an inflow of the fibroblast that is an origin of gingiva tissue.
  • the inner layer of the bone regeneration membrane has a fiber radial structure, osteoblast can be more easily attached to the inner layer due to a large specific surface area and mixing with calcium phosphate. Accordingly, for dental fields, during a bone generation period following coverage with an artificial bone, stable bone regeneration can be derived.
  • mixing with calcium phosphate contributes to maintenance of bioactivity, and use of a pharmaceutical biodegradable polymer relieves patients from a second surgery because the pharmaceutical biodegradable polymer is gradually absorbed into body and removed after a sufficient bone regeneration period. Accordingly, a high quality dental clinic service can be provided.
  • FIG. 1 shows images of an outer layer (a) and inner layer (b) of a bone regeneration membrane according to the present invention
  • FIG. 2 shows enlarged images (x 6,000) of an outer layer of an bone regeneration membrane to explain a change in a pore size of a surface of the outer layer with respect to a supply rate of vapor when the outer layer is prepared by self-assembly;
  • FIG. 3 shows X-ray diffraction analysis results of a calcium phosphate-based synthesis solution, wherein the calcium phosphate-based synthesis solution is to be mixed with a pharmaceutical polymer to form an inner layer having a fiber radial structure of a bone regeneration membrane by electrospinning;
  • FIG. 4 shows enlarged surface images (x 3,000) of an outer layer of a bone regeneration membrane formed by electrospinning, when polycaprolactone that is a pharmaceutical polymer is used alone and when a mixture including polycaprolactone and biphasic calcium phosphate (BCP) in a ratio of 25:75 is used, respectively; and
  • FIG. 5 shows enlarged images (x750) illustrating attachment characteristics of a bone regeneration membrane according to the present invention when osteoblast is incubated in the bone regeneration membrane.
  • the present invention provides a bone regeneration membrane including: an outer layer having a porous semi-permeable structure and including a pharmaceutical biodegradable polymer and an amphiphilic polymer including a hydrophilic group and a hydrophobic group; and an inner layer having a fiber radial mesh structure and including a mixture of a pharmaceutical biodegradable polymer and a calcium phosphate, wherein the inner layer is formed on the outer layer.
  • the present invention also provides a method of manufacturing a bone regeneration membrane, wherein the method includes: adding an amphiphilic polymer having a hydrophilic group and a hydrophobic group to a first pharmaceutical biodegradable polymer to prepare a mixture and stirring the mixture to prepare a solution; coating the solution on a substrate to form a film; adsorbing vapor particles to the film; polymerizing the film to which vapor particles are adsorbed in order to evaporate vapor particles, thereby forming an outer layer having a porous semi-permeable structure; preparing a calcium phosphate solution; mixing the calcium phosphate solution and a second pharmaceutical biodegradable polymer; and forming an inner layer having a fiber radial mesh structure on the outer layer having the porous semi-permeable structure by using the mixture of the calcium phosphate solution and the second pharmaceutical biodegradable polymer.
  • a bone regeneration membrane includes: an outer layer having a porous semi-permeable structure including a pharmaceutical biodegradable polymer and an amphiphilic polymer including a hydrophilic group and a hydrophobic group; and an inner layer having a fiber radial mesh structure including a mixture of a pharmaceutical biodegradable polymer and a calcium phosphate, wherein the inner layer is formed on the outer layer.
  • the pharmaceutical biodegradable polymer used to form the outer layer may include at least one polymer selected from the group consisting of poly(lactic acid), poly(-L-lactic acid), poly(-DL-lactic acid), copoly(lactide-mandelate), poly(glycolic acid), poly( ⁇ -hydroxybutyrate), poly( ⁇ -caprolactone), poly( ⁇ -caprolactone), poly(dioxanone- ⁇ -caprolactone), poly(lactic-co-glycolic acid), poly(lactide-co-glycolide)- ⁇ -carprolactone, poly(trimethylene carbonate) and poly(orthoesters), or a co-polymerization derivative thereof.
  • the amphiphilic polymer may, have a block copolymerization structure including polystyrene as a basic framework. That is, various block copolymers may be formed by anionic block copolymerization based on polystyrene as the basic framework.
  • amphiphilic polymer may be a compound having a chemical structure in which the ratio of polystyrene to a block polymer is in a range of 2:1 to 5:1.
  • amphiphilic polymer may be a compound represented by Formula 1 :
  • M represents a block polymer and may include at least one compound selected from the group consisting of 4-vinylpyridine, butadiene, polybutadiene, methacrylic acid, dodecylacrylamide, ⁇ -carboxyhexylacrylamide, polyparapheylene, polythiophene, poly-3-hexylthiophene, polymethylmethacrylate, polyethylene oxide, polyvinylidene fluoride, polyacrylamide, and poly-N,N dimethylacrylamide, and the ratio of n:m may be in a range of 2:1 to 5:1.
  • the outer layer having the porous semi-permeable structure may be formed by self-assembly.
  • a mixture of the pharmaceutical biodegradable polymer and the amphiphilic polymer is spin-coated to form a film and then the film is placed in a humidity chamber. In the humidity chamber, fine vapor particles are uniformly adsorbed to the film and arranged. Then, the resultant film is polymerized and dried.
  • the outer layer having the porous semi-permeable structure is manufactured by self-assembly, an outer layer having a regularly arranged pore structure can be obtained. However, the outer layer may also be formed using other methods.
  • the outer layer having the porous semi-permeable structure may have a pore size in a range of 200 nm to 50 /mi.
  • the pharmaceutical biodegradable polymer used to form the inner layer may include at least one polymer selected from the group consisting of poly(lactic acid), poly(-L-lactic acid), poly(-DL-lactic acid), copoly(lactide-mandelate), poly(glycolic acid), poly( ⁇ -hydroxybutyrate), poly( ⁇ -caprolactone), poly( ⁇ -caprolactone), poly(dioxanone- ⁇ -caprolactone), poly(lactic-co-glycolic acid), poly(lactide-co-glycolide)- ⁇ -carprolactone, poly(trimethylene carbonate) and poly(orthoesters), or a co-polymerization derivative thereof.
  • calcium phosphate may be added in a form of a solution prepared by using a zol-gel method.
  • the solution prepared by using the zol-gel method may be a biodegradable calcium phosphate-based solution selected from hydroxyapatite (HA), ⁇ -tricalcium phosphate ( ⁇ -TCP), and biphasic calcium phosphate (BCP).
  • the inner layer may be formed by electrospinning.
  • the biodegradable calcium phosphate-based solution may be electrospun to form the inner layer.
  • the outer layer of the bone regeneration membrane according to the present invention has the porous semi-permeable structure having a dense porous structure and includes the pharmaceutical biodegradable polymer and the amphiphilic polymer including the hydrophilic group and the hydrophobic group, when, in dental fields, the outer layer is inserted into a gingiva tissue subcutis after coverage with a bone regenerating material, the outer layer may allow body fluid, and oxygen to easily pass through and effectively prevent an inflow and attachment of fibroblast that is an origin of a gingiva tissue.
  • the inner layer of the bone regeneration membrane according to the present invention has the fiber radial mesh structure and includes the mixture of the pharmaceutical biodegradable polymer and the calcium phosphate, an attachment capability of osteoblast that is an origin of a bone tissue is significantly improved due to a large specific surface area and mixing with calcium phosphate, and thus, an inflow of the gingiva tissue into a bone tissue is prevented, and, in dental fields, stable bone regeneration may be derived during a bone regeneration period after coverage with an artificial bone.
  • a method of manufacturing a bone regeneration membrane includes: a) adding an amphiphilic polymer including a hydrophilic group and a hydrophobic group to a pharmaceutical biodegradable polymer to prepare a mixture and stirring the mixture to prepare a solution; b) coating the solution prepared in step a) on a substrate to form a film; c) adsorbing vapor particles to the film prepared in step b); d) polymerizing the film to which vapor particles are attached in step c) in order to evaporate vapor particles, thereby forming an outer layer having a porous semi-permeable structure; e) preparing a calcium phosphate solution; f) mixing the calcium phosphate solution prepared in step e) and a pharmaceutical biodegradable polymer; and g) forming an inner layer having a fiber radial mesh structure on the outer layer having the porous semi-permeable structure by using the mixture prepared in step f).
  • the pharmaceutical biodegradable polymer in step a) may include at least one polymer selected from the group consisting of poly(lactic acid), poly(-L-lactic acid), poly(-DL-lactic acid), copoly(lactide-mandelate), poly(glycolic acid), poly( ⁇ -hydroxybutyrate), poly( ⁇ -caprolactone), poly( ⁇ -caprolactone), poly(dioxanone- ⁇ -caprolactone), poly(lactic-co-glycolic acid), poly(lactide-co-glycolide)- ⁇ -carprolactone, poly(trimethylene carbonate) and poly(orthoesters), or a co-polymerization derivative thereof.
  • the amphiphilic polymer in step a) may have a block copolymerization structure including polystyrene as a basic framework. That is, various block copolymers may be formed by anionic block copolymerization based on polystyrene as the basic framework.
  • amphiphilic polymer may be a compound having a chemical structure in which the ratio of polystyrene to a block polymer is in a range of 2:1 to 5:1.
  • amphiphilic polymer in step a) may be a compound represented by Formula 1:
  • M represents a block polymer and may include at least one compound selected from the group consisting of 4-vinylpyridine, butadiene, polybutadiene, methacrylic acid, dodecylacrylamide, ⁇ -carboxyhexylacrylamide, polyparapheylene, polythiophene, poly-3-hexylthiophene, polymethylmethacrylate, polyethylene oxide, polyvinylidene fluoride, polyacrylamide, and poly-N,N dimethylacrylamide, and the ratio of n:m may be in a range of 2:1 to 5:1.
  • the amount of the amphiphilic polymer may be in a range of 1 to 30 parts by weight based on the pharmaceutical biodegradable polymer.
  • the mixture of the amphiphilic polymer and the pharmaceutical biodegradable polymer may be dissolved at a concentration of 1 to 10 mg per 1 ml_ with respect to a solvent and stirred.
  • the solvent may be chloroform, but is not limited thereto.
  • the amphiphilic polymer may be added in an amount of 1 to 30 weight% based on the pharmaceutical biodegradable polymer, and may be dissolved in an amount of 1 to 15 weight% in a mixed solution including 70 to 100 weight% of chloroform and 0 to 30 weight% of methanol.
  • step d) when photopolymerization using ultra-violet (UV) rays is performed, 0.1 to 1 weight% of a photo initiator may be added to the mixture of the amphiphilic polymer and the pharmaceutical biodegradable polymer prepared in step a), In step b), the film may be formed by spin-coating.
  • UV ultra-violet
  • step b) the solution including the pharmaceutical biodegradable polymer and the amphiphilic polymer prepared in step a) is dropped in an amount of 1 to 7 ml to a glass plate having a diameter of 2 to 10 cm and then, the spin-coating is performed at a rotation rate of 100 to 4000 rpm to form the film.
  • step c) the film prepared in step b) is placed into a chamber having humidity of
  • step c) the film prepared in step b) is placed into a chamber having humidity of 20 to 90% and then, left to sit for 5 seconds to 30 minutes while vapor is supplied at a supply rate of 0.2 to 1.0 L/min.
  • step d) the film prepared in step c) may be subjected to thermal polymerization or photopolymerization.
  • thermal polymerization For the photopolymerization, ultra-violet (UV) rays may be irradiated to perform the photopolymerization.
  • UV ultra-violet
  • the outer layer having the porous semi-permeable structure may have a pore size in a range of 200 nm to 50 ⁇ m.
  • the calcium phosphate solution may be prepared by using a zol-gel method.
  • the calcium phosphate solution prepared by using the zol-gel method in step e) may be a biodegradable calcium phosphate-based solution selected from hydroxyapatite (HA), ⁇ -tricalcium phosphate ( ⁇ -TCP), and biphasic calcium phosphate (BCP).
  • Step e) When the calcium phosphate solution is prepared by using the zol-gel method, a mole ratio of Ca/P may be controlled to be in a range of 0.5 to 2.0.
  • a Ca starting material and a P starting material is dissolved in methanol having an amount 10 mole times greater than that of the corresponding starting material.
  • distilled water having an amount 5 mole times greater than that of P(OC 2 H 5 ) 3 may be further added to the resultant P starting material solution to perform a hydrolysis reaction. Then, the prepared Ca and P starting materials are reacted together and stirred and then, the reaction product is left to sit for 1 to 3 days at a temperature of 35 ° C for aging, thereby forming the calcium phosphate solution.
  • the Ca starting material may include at least one material selected from the group consisting of Ca(N ⁇ 3 ) 2 4H 2 ⁇ and Ca(OC 2 H 5 )2, and the P starting material may include at least one material selected from the group consisting of P(OC 2 Hs) 3 , P(OCH 3 ) 3 , OP(OC 2 Hs) 3 , and OP(OCH 3 ) 3 .
  • a Ca starting material including at least one material selected from the group consisting of Ca(NO 3 ) 2 4H 2 O and Ca(OC 2 Hs) 2 is prepared, and a P starting material including at least one material selected from the group consisting of P(OC 2 Hs) 3 ,
  • P(OCH 3 ) 3 , OP(OC 2 Hs) 3 , and OP(OCH 3 ) 3 is prepared.
  • distilled water having an amount 3 to 10 mole times greater than the P starting material is further added to the P starting material to perform a hydrolysis reaction for 10 minutes to 5 hours. Then, the hydrolyzed P starting material is reacted with the Ca starting material to form the calcium phosphate solution.
  • the calcium phosphate solution can be prepared by using a zol-gel method in which Ca(NO 3 ) 2 4H 2 O is reacted with P(OC 2 Hs) 3 and then the reaction product is aged.
  • a BCP calcium phosphate solution can be manufactured
  • the pharmaceutical biodegradable polymer in step f) may include at least one polymer selected from the group consisting of poly(lactic acid), poly(-L-lactic acid), poly(-DL-lactic acid), copoly(lactide-mandelate), poly(glycolic acid), poly( ⁇ -hydroxybutyrate), poly( ⁇ -caprolactone), poly( ⁇ -caprolactone), poly(dioxanone- ⁇ -caprolactone), poly(lactic-co-glycolic acid), poly(lactide-co-glycolide)- ⁇ -carprolactone, poly(trimethylene carbonate) and poly(orthoesters), or a co-polymerization derivative thereof.
  • the calcium phosphate solution prepared in step e) may be mixed with the pharmaceutical biodegradable polymer in a ratio of 10:90 to 90:10.
  • the pharmaceutical biodegradable polymer may be dissolved in a mixed solution including 70 to100 weight% of chloroform and 0 to 30 weight% of methanol and the amount of the pharmaceutical biodegradable polymer may be in a range of 1 to 15 weight% based on the mixed solution.
  • step f) the solution prepared by dissolving the pharmaceutical biodegradable polymer in the mixed solution is mixed with the calcium phosphate solution prepared in step e) in a ratio of 10:90 to 90:10, thereby producing a solution for electrospinning in step g) to be described later.
  • step g) the inner layer having the fiber radial mesh structure is formed by electrospinning. Specifically, in step g), the electrospinning is performed by applying a voltage in a range of 10 to 30 kV for 1 to 60 minutes while the mixed solution prepared in step f) is supplied at a supply rate in a range of 0.5 to 3 ml/h.
  • the outer layer prepared in step d) is placed on a bottom plane electrode, and a distance between a nozzle and the bottom plane electrode is maintained to be in a range of 10 to 30 cm. Then, the electrospinning is performed at a voltage of 10 to 30 KV for 1 to 30 minutes, and then drying is performed at a temperature of 60 to 200 ° C for 10 to 30 minutes.
  • FIG. 1 shows images of a bone regeneration membrane according to the present invention.
  • the bone regeneration membrane according to the present invention includes an outer layer (a) having regularly arranged pores formed by self-assembly and an inner layer (b) having a fiber radial structure formed by electrospinning.
  • the outer layer is exposed toward a gingiva in an oral structure, and the inner layer is exposed toward an alveolar bone covered with a synthesis bone.
  • FIG. 2 are images showing the adsorption behavior of vapor particles and a pore size, according to the flow rate of vapor in a chamber having 80% of humidity, when the outer layer having the porous semi-permeable is formed.
  • the formed film When no vapor is provided, the formed film has no pores and a dense structure. However, when a vapor is provided at a supply rate of 0.2 L/min, a uniform pore structure having a pore size of about 500 nm can be obtained. As the supply rate is increased, the pore size is increased. However, when the vapor is supplied at a supply rate of 1.0 L/min or more, adsorbed vapor particles are combined to form a larger vapor particle and the independent regular pore arrangement structure is thus collapsed.
  • FIG. 3 shows X-ray diffraction analysis results of hydroxyapatite (HA), ⁇ -tricalcium phosphate ( ⁇ -TCP), and biphasic calcium phosphate (BCP), which are prepared by using the zol-gel method.
  • HA hydroxyapatite
  • ⁇ -TCP ⁇ -tricalcium phosphate
  • BCP biphasic calcium phosphate
  • the mole ratio of Ca/P is controlled to be in a range of 1.6 to 1.7; for ⁇ -TCP, the mole ratio of Ca/P is controlled to be in a range of 1.4 to1.6; and for BCP, the mole ratio of Ca/P is controlled to be in a range of 1.5 to 1.6.
  • ⁇ -TCP and BCP that are well known as a biodegradable calcium phosphate-based material can be chosen.
  • BCP is used for the electrospinning.
  • FIG. 4 shows surface images of an inner layer having a fiber radial mesh structure formed by electrospinning of a bone regeneration membrane according to the present invention, when polycaprolactone (PCL) that is a pharmaceutical polymer is used alone and when a mixture of PCL and BCP prepared by using the zol-gel method in a ratio of PCL and BCP.
  • PCL polycaprolactone
  • FIG. 5 shows surface images of an inner layer of a bone regeneration membrane according to the present invention, wherein the inner layer is formed by electrospinning the mixture of PCL and BCP, when osteoblast is incubated in the bone regeneration membrane for one day.
  • FIG. 1 it can be seen that osteoblast is stably attached to the inner layer of the bone regeneration membrane. That is, after the osteoblast is incubated for one day, osteoblast is stably spread and amplified according to a fiber radial framework.
  • Examples 1 through 5 Manufacture of outer layer having a porous semi-permeable structure of a bone regeneration membrane by self-assembly
  • polycaprolactone molecular weight of 80,000
  • polystyrene-b-polybutadiene was used as an amphiphilic polymer.
  • the amount of the amphiphilic polymer was 10 weight% based on polycaprolactone.
  • the resultant solution was dropped in an amount of 5 ml to a glass plate having a diameter of 8 cm and spin-coating was performed at room temperature at a rotation rate of 500 rpm, thereby forming a thin film.
  • the glass plate coated with the thin film was immediately placed into a chamber having humidity of 80% and then, vapor was supplied to the chamber at a supply rate of 0.2 toi .O L/min for 10 seconds and the thin film was taken out of the chamber. Subsequently, the thin film was placed in a UV-radiation chamber and then left to sit for about 10 in order to perform a photopolymerization, thereby forming a semi-permeable film having regularly arranged fine pores.
  • Table 1 [Table 1 ]
  • vapor particles are combined to each other to form a larger vapor particle, thereby forming a larger pore.
  • a threshold vapor supply rate that is, when the vapor supply rate exceeds 1.0 L/min, too large vapor particles are formed and thus pores are irregularly arranged.
  • polycaprlactone was dissolved at a concentration of 5 to 7.5 weight% in a mixed solution including 75 weight% of chloroform and 25 weight% of methanol, thereby producing a polymer starting solution.
  • a Ca/P mole ratio was controlled to be 1.55.
  • 0.02 mol of Ca(NO 3 ) 2 4H 2 O was dissolved in 0.2 mol of methanol to prepare a Ca starting material.
  • 0.013 mol of P(OC 2 Hs) 3 as a P starting material was dissolved in 0.13 mol of methanol and then, 0.065 mol of distilled water was added thereto and the resultant solution was stirred for two hours, thereby performing a hydrolysis reaction.
  • the P starting material in which the hydrolysis reaction was finished was slowly dropped to the Ca starting material while stirring for 30 minutes, and then the reaction product was aged at a temperature of 35 ° C for 3 days, thereby producing a BCP starting solution.
  • the prepared polycaprolactone solution was mixed with the BCP starting solution in weight ratios of 75:25 and 25:75, and then each of the resultant solutions was loaded to a syringe and the syringe was connected to an automatic syringe pump in order to perform electrospinning.
  • a distance between an end of a nozzle of the syringe and a plane electrode was controlled to be 13 cm, and the outer layers of the bone regeneration membrane formed by self-assembly prepared according to Examples 1 through 5 were placed on the plane electrode.
  • the electrospinning was slowly performed by supplying the resultant solution at a supply rate of 1.0 ml/h at a voltage of 20 kV in humidity of 30 to 40%, thereby manufacturing an inner layer having a fiber radial structure of a bone regeneration membrane.
  • the bone regeneration membrane formed by electrospinning was dried at a temperature of 60 to 150 ° C for 10 to 60 minutes.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Composite Materials (AREA)
  • Materials Engineering (AREA)
  • Dispersion Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention concerne une membrane de régénération osseuse et un procédé de fabrication de membrane de régénération osseuse. La membrane de régénération osseuse comporte : une couche extérieure présentant une structure semi-perméable et comprenant un polymère pharmaceutique biodégradable et un polymère amphiphile ayant un groupe hydrophile et un groupe hydrophobe ; et une couche intérieure présentant une structure maillée de fibres radiales et comprenant un mélange d'un polymère pharmaceutique biodégradable et un phosphate de calcium, la couche intérieure étant formée sur la couche extérieure.
PCT/KR2008/004932 2007-10-26 2008-08-22 Membrane de régénération osseuse et procédé de fabrication de membrane de régénération osseuse WO2009054609A1 (fr)

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KR1020070108334A KR100946268B1 (ko) 2007-10-26 2007-10-26 골재생 유도막 및 이의 제조방법
KR10-2007-0108334 2007-10-26

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2404627A1 (fr) 2010-07-09 2012-01-11 Universite De Nantes I Membrane de régénération osseuse et procédé de formation d'une membrane de régénération osseuse
WO2013163704A1 (fr) * 2012-05-04 2013-11-07 Bioactive Tecnologia Em Polímeros Ltda - Me Membrane bio-réabsorbable bioactive poreuse et son procédé d'obtention
WO2014102431A1 (fr) 2012-12-24 2014-07-03 Servicio Andaluz De Salud Membrane réabsorbable pour régénération osseuse guidée
US9090863B2 (en) 2010-05-17 2015-07-28 Pall Corporation System for seeding cells onto three dimensional scaffolds
EP2789353A4 (fr) * 2011-12-05 2015-07-29 Hitachi Chemical Co Ltd Membrane d'induction de la régénération d'os/tissu et son procédé de fabrication
CN108870799A (zh) * 2017-05-12 2018-11-23 浙江大学 辐射制冷颗粒和蒸气凝结回收装置
WO2020237785A1 (fr) * 2019-05-30 2020-12-03 四川大学 Matériau à gradient pour guider la régénération de tissus osseux et mous parodontaux et son procédé de préparation
CN113370533A (zh) * 2021-04-25 2021-09-10 中国人民解放军空军军医大学 3d打印可塑形引导骨再生膜的制备方法

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KR101810080B1 (ko) * 2015-06-01 2017-12-19 주식회사 아모라이프사이언스 치과용 멤브레인
CN115671387B (zh) * 2022-11-10 2023-12-08 奥精医疗科技股份有限公司 一种用于长节段骨缺损的骨修复支架及其制备方法和应用

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JP2002000717A (ja) * 2000-06-21 2002-01-08 National Institute For Materials Science 骨再生誘導材料
KR20020076662A (ko) * 2001-03-30 2002-10-11 이승진 키토산으로 표면 코팅된 조직 재생용 생분해성 고분자제제 및 그 제조방법
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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9090863B2 (en) 2010-05-17 2015-07-28 Pall Corporation System for seeding cells onto three dimensional scaffolds
WO2012004407A2 (fr) 2010-07-09 2012-01-12 Universite De Nantes Membrane de régénération osseuse et procédé de formation d'une membrane de régénération osseuse
WO2012004407A3 (fr) * 2010-07-09 2012-06-14 Universite De Nantes Membrane de régénération osseuse et procédé de formation d'une membrane de régénération osseuse
EP2404627A1 (fr) 2010-07-09 2012-01-11 Universite De Nantes I Membrane de régénération osseuse et procédé de formation d'une membrane de régénération osseuse
EP2789353A4 (fr) * 2011-12-05 2015-07-29 Hitachi Chemical Co Ltd Membrane d'induction de la régénération d'os/tissu et son procédé de fabrication
US9877808B2 (en) 2011-12-05 2018-01-30 Hitachi Chemical Company, Ltd. Membrane for inducing regeneration of bone/tissue, and method for producing same
WO2013163704A1 (fr) * 2012-05-04 2013-11-07 Bioactive Tecnologia Em Polímeros Ltda - Me Membrane bio-réabsorbable bioactive poreuse et son procédé d'obtention
WO2014102431A1 (fr) 2012-12-24 2014-07-03 Servicio Andaluz De Salud Membrane réabsorbable pour régénération osseuse guidée
CN108870799A (zh) * 2017-05-12 2018-11-23 浙江大学 辐射制冷颗粒和蒸气凝结回收装置
WO2020237785A1 (fr) * 2019-05-30 2020-12-03 四川大学 Matériau à gradient pour guider la régénération de tissus osseux et mous parodontaux et son procédé de préparation
US11696974B2 (en) 2019-05-30 2023-07-11 Sichuan University Method for preparing a functionally gradient material for guided periodontal hard and soft tissue regeneration
CN113370533A (zh) * 2021-04-25 2021-09-10 中国人民解放军空军军医大学 3d打印可塑形引导骨再生膜的制备方法
CN113370533B (zh) * 2021-04-25 2022-12-06 中国人民解放军空军军医大学 3d打印可塑形引导骨再生膜的制备方法

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